{"title":"成人、青少年和儿童A型严重血友病患者的血药代动力学和重复事件时间分析","authors":"Nancy Wong PhD, Pratik Bhagunde PhD, Joakim Nyberg PhD, Suresh Katragadda PhD, Marek Demissie MD, PhD, Annemieke Willemze MD, Craig Benson MD, Sreeraj Macha PhD","doi":"10.1002/jcph.70008","DOIUrl":null,"url":null,"abstract":"<p>Efanesoctocog alfa is a first-in-class high-sustained factor VIII (HSF) replacement therapy for treatment of hemophilia A. This article presents population pharmacokinetics (PopPK) of efanesoctocog alfa and repeated time-to-event (RTTE) analysis of bleeding episodes in adults/adolescents (≥12 years of age) and children (<12 years). The final PopPK dataset contained pooled data from 277 patients (4405 post-dose factor VIII [FVIII] activity records) from two Phase 1/2a studies (NCT03205163; EudraCT 2018-001535-51), and three Phase 3 studies, XTEND-1 (NCT04161495), XTEND-Kids (NCT04759131), and XTEND-ed (NCT04644575). The PopPK model developed was a linear one-compartment model including body weight effect on clearance and volume of central compartment; Asian race was identified as a statistically significant covariate on clearance. The final PopPK model adequately described the FVIII activity–time profiles in adults, adolescents, and children with once-weekly (QW) efanesoctocog alfa 50 IU/kg, consistent with experience in XTEND-1 and XTEND-Kids. Bleeding episodes in participants in XTEND-1 and XTEND-Kids were characterized by an RTTE model with a Weibull base hazard and effect of FVIII activity modeled by a power effect. The RTTE model showed the probability of being bleed-free in 1 year with efanesoctocog alfa 50 IU/kg QW regimen was >70% across all age groups, consistent with the observed clinical outcomes in the Phase 3 trials of highly effective protection from bleeding episodes in patients with severe hemophilia A, which validates the model's prediction of the long-term bleed hazard.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 7","pages":"860-872"},"PeriodicalIF":0.0000,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70008","citationCount":"0","resultStr":"{\"title\":\"Efanesoctocog Alfa Population Pharmacokinetics and Repeated Time-To-Event Analysis of Bleeds in Adults, Adolescents, and Children with Severe Hemophilia A\",\"authors\":\"Nancy Wong PhD, Pratik Bhagunde PhD, Joakim Nyberg PhD, Suresh Katragadda PhD, Marek Demissie MD, PhD, Annemieke Willemze MD, Craig Benson MD, Sreeraj Macha PhD\",\"doi\":\"10.1002/jcph.70008\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Efanesoctocog alfa is a first-in-class high-sustained factor VIII (HSF) replacement therapy for treatment of hemophilia A. This article presents population pharmacokinetics (PopPK) of efanesoctocog alfa and repeated time-to-event (RTTE) analysis of bleeding episodes in adults/adolescents (≥12 years of age) and children (<12 years). The final PopPK dataset contained pooled data from 277 patients (4405 post-dose factor VIII [FVIII] activity records) from two Phase 1/2a studies (NCT03205163; EudraCT 2018-001535-51), and three Phase 3 studies, XTEND-1 (NCT04161495), XTEND-Kids (NCT04759131), and XTEND-ed (NCT04644575). The PopPK model developed was a linear one-compartment model including body weight effect on clearance and volume of central compartment; Asian race was identified as a statistically significant covariate on clearance. The final PopPK model adequately described the FVIII activity–time profiles in adults, adolescents, and children with once-weekly (QW) efanesoctocog alfa 50 IU/kg, consistent with experience in XTEND-1 and XTEND-Kids. Bleeding episodes in participants in XTEND-1 and XTEND-Kids were characterized by an RTTE model with a Weibull base hazard and effect of FVIII activity modeled by a power effect. The RTTE model showed the probability of being bleed-free in 1 year with efanesoctocog alfa 50 IU/kg QW regimen was >70% across all age groups, consistent with the observed clinical outcomes in the Phase 3 trials of highly effective protection from bleeding episodes in patients with severe hemophilia A, which validates the model's prediction of the long-term bleed hazard.</p>\",\"PeriodicalId\":22751,\"journal\":{\"name\":\"The Journal of Clinical Pharmacology\",\"volume\":\"65 7\",\"pages\":\"860-872\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2025-03-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70008\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Journal of Clinical Pharmacology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/jcph.70008\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Clinical Pharmacology","FirstCategoryId":"1085","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jcph.70008","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
摘要
Efanesoctocog alfa 是治疗 A 型血友病的第一类高持续因子 VIII (HSF) 替代疗法。本文介绍了 efanesoctocog alfa 的群体药代动力学 (PopPK) 以及对成人/青少年(≥12 岁)和儿童(各年龄组均为 70%,与 3 期临床试验中观察到的临床结果一致,可高效防止重度 A 型血友病患者出血发作,这验证了模型对长期出血危险的预测。
Efanesoctocog Alfa Population Pharmacokinetics and Repeated Time-To-Event Analysis of Bleeds in Adults, Adolescents, and Children with Severe Hemophilia A
Efanesoctocog alfa is a first-in-class high-sustained factor VIII (HSF) replacement therapy for treatment of hemophilia A. This article presents population pharmacokinetics (PopPK) of efanesoctocog alfa and repeated time-to-event (RTTE) analysis of bleeding episodes in adults/adolescents (≥12 years of age) and children (<12 years). The final PopPK dataset contained pooled data from 277 patients (4405 post-dose factor VIII [FVIII] activity records) from two Phase 1/2a studies (NCT03205163; EudraCT 2018-001535-51), and three Phase 3 studies, XTEND-1 (NCT04161495), XTEND-Kids (NCT04759131), and XTEND-ed (NCT04644575). The PopPK model developed was a linear one-compartment model including body weight effect on clearance and volume of central compartment; Asian race was identified as a statistically significant covariate on clearance. The final PopPK model adequately described the FVIII activity–time profiles in adults, adolescents, and children with once-weekly (QW) efanesoctocog alfa 50 IU/kg, consistent with experience in XTEND-1 and XTEND-Kids. Bleeding episodes in participants in XTEND-1 and XTEND-Kids were characterized by an RTTE model with a Weibull base hazard and effect of FVIII activity modeled by a power effect. The RTTE model showed the probability of being bleed-free in 1 year with efanesoctocog alfa 50 IU/kg QW regimen was >70% across all age groups, consistent with the observed clinical outcomes in the Phase 3 trials of highly effective protection from bleeding episodes in patients with severe hemophilia A, which validates the model's prediction of the long-term bleed hazard.